Cancer stem cells (CSCs) have been identified in wide range of human malignancies, and their enhanced growth potential suggests a major role in cancer initiation, maintenance, relapse, and progression. However, the scarcity of data demonstrating CSCs are clinically important and the lack of clinically applicable targeting strategies are the critical gaps that must be addressed before the CSC hypothesis can become a basis for the treatment of cancer patients. The candidate for this K24 award is an Associate Professor at Johns Hopkins University who has begun to build a translational and clinical research program focused on CSCs and has established a strong track record of patient-oriented research, peer-reviewed funding, and successful mentoring. This group originally isolated CSCs in multiple myeloma (MM), identified novel CSC-targeting strategies, translated these laboratory findings into innovative clinical trials, and developed novel biomarkers to quantify CSCs in the clinical setting. This research has significantly advanced basic knowledge regarding CSCs and led efforts to test their clinical significance. A critical part of the success f this program has been the mentoring and training of young and early investigators in patient-oriented research. Specifically, the candidate has been committed to providing guidance for the acquisition and mastery of skills to formulate significant and innovative hypotheses from important clinical questions, execute sound and rigorous scientific inquiry to decipher disease pathogenesis and develop novel therapeutic approaches, translate these findings into clinical trials, and carry out meaningful correlative studies addressing the original hypothesis in the clinical setting. Through this K24 application, the candidate seeks support and protected time to improve his mentoring skills and expand his research expertise. In terms of mentoring, he will carry out a deliberate plan of didactic course work, mentorship from a senior academic leader, and a structured plan of mentoring his trainees within the context of the proposed research plan. With respect to new research skills, the candidate will gain expertise in a new area, bioinformatics, through coursework and supervised training with leading bioinformatics experts while carrying out the proposed Specific Aims. Finally, the candidate will expand his research program by exploring the tumor microenvironment and probing specific genetic changes within MM CSCs through next generation sequence analysis. The research Aims will lead to the development of new biomarkers that can act as surrogates for CSCs and address the hypothesis that CSCs correlate with clinical outcomes. A second hypothesis is that novel therapeutic targets based on these experimental approaches can target MM CSCs. Accordingly; the scientific Aims of this proposal are to (1) determine the clinical relevance of MM CSCs and (2) identify novel strategies to inhibit MM CSCs. These training and scientific endeavors will significantly expand the candidate's research program and improve his mentorship skills to further build a leading and paradigm-shifting program in CSC-focused patient oriented research.